Abstract:

The invention relates to a novel diagnostic marker CT-proADM (C-terminal
fragment of preproADM, SEQ ID No, 1) for diagnosing and/or stratifying
the risk of diseases. Also disclosed is a method for diagnosing and/or
stratifying the risk of diseases, particularly cardiovascular diseases,
cardiac insufficiency, and infections and/or inflammations of the lungs
and respiratory tract. In said method, the CT-proADM (SEQ ID No. 1)
marker, or a partial peptide of fragment thereof, or said marker
contained in a marker combination (panel, cluster) is determined in a
patient who is to be examined. The invention further relates to a
diagnostic apparatus as well as a kit for carrying out said method.

Claims:

2. Method for diagnosing and/or stratifying the risk of diseases,
characterized in thatthe CT-proADM (SEQ ID No. 1), or a partial peptide
of fragment thereof, is determined in a patient who is to be examined.

3. Method according to claim 2 characterized in that the method is an
in-vitro diagnosis.

4. Method according to claim 2, characterized in that the diagnosis or
risk stratification of diseases, particularly cardiovascular diseases,
cardiac insufficiency, infections and/or inflammations of the lungs and
respiratory tract is determined in-vitro.

8. Method according to claim 2 characterized in thatadditionally at least
one additional marker--selected from a group of inflammatory markers,
cardiovascular markers, neurohormonal markers, or ischemic markers--is
determined in a patient who is to be examined.

9. Method according to claim 8 characterized in that the inflammatory
marker is selected from at least one marker from the group of C-reactive
protein (CRP), cytokines, such as TNF-alpha, interleukins, such as IL-6,
procalcitonin (1-116, 3-116) and adhesion molecules, such as VCAM or
ICAM.

10. Method according to claim 8 characterized in that the cardiovascular
marker is selected from at least one marker from the group of creatine
kinase, kinase, myeloperoxidase, copeptin, myoglobin, natriuretic
protein, especially ANP (or ANF), proANP, NT-proANP, BNP, proBNP,
NT-proBNP, or in each case a partial sequence thereof, cardiac troponin,
CRP, as well as (pro)hormones regulating circulation, such as
pro-gastrin-releasing peptide (proGRP), pro-endothelin-1, pro-leptin,
pro-neuropeptide-Y, pro-somatostatin, pro-neuropeptide-YY,
pro-opiomelanocortin, or in each case a partial sequence thereof.

11. Method according to claim 8 characterized in that the ischemic marker
is selected from at least one marker from the group of troponin I and T,
CB-MB.

12. Method according to claim 8 characterized in that the neurohormonal
marker is at least a natriuretic protein, particularly ANP (or ANF),
proANP, NT-proANP, BNP, proBNP, NT-proBNP, or in each case a partial
sequence thereof.

13. Method according to claim 2 characterized in thatparallel or
simultaneous determinations of the markers are carried out.

14. Method according to claim 2 characterized in thatthe determinations
are carried out by means of at least one patient sample.

15. Method according to claim 2 characterized in thatthe determinations
are carried out by means of an automatic analysis device, particularly a
Kryptor.

16. Method according to claim 2 characterized in that the determinations
carried out by means of a rapid test, particularly through individual or
multi-parameter determinations.

17. Method according to claim 2 characterized in that the diagnosis for
the stratification of patients, in particular for the stratification of
patients is made for clinical decisions, particularly further treatment
by means of using drugs for the treatment or therapy of diseases,
especially in intensive medicine or emergency medicine and for the
hospitalization of patients.

18. Method according to claim 2 characterized in that the diagnosis and/or
risk stratification is made for prognosis, for differential-diagnostic
early diagnosis and detection, for the assessment of the severity, and
for the evaluation of the course of diseases accompanying the therapy,
particularly cardiovascular diseases, cardiac insufficiency, infections
and/or inflammations of the lungs and respiratory tract.

Description:

[0001]The invention relates to novel diagnostic marker CT-proADM
(C-terminal fragment of preproADM, SEQ ID No. 1) for diagnosing and/or
stratifying the risk of diseases. Also disclosed is a method for
diagnosing and/or stratifying the risk of diseases, particularly
cardiovascular diseases, cardiac insufficiency, and infections and/or
inflammations of the lungs and respiratory tract. In said method, the
CT-proADM (SEQ ID No. 1) marker, or a partial peptide of fragment
thereof, or said marker contained in a marker combination (panel,
cluster) is determined in a patient who is to be examined. The invention
further relates to a diagnostic apparatus as well as a kit for carrying
out said method.

[0005]There exists however a great need to come up with a reliable
diagnosis, or carry out a (risk) stratification, for diseases,
particularly cardiovascular diseases, cardiac insufficiency, infections
and/or inflammations of the lungs and respiratory tract, in particular in
terms of further clinical decisions, and in particular with respect to
the severity of diseases, in particular with cardiovascular diseases,
cardiac insufficiency, infections and/or inflammations of the lungs and
respiratory tract.

[0006]It is one task of the present invention to provide a novel marker.
An additional task of the present invention consists of providing an
improved method for diagnosing and/or stratifying the risk of diseases,
particularly cardiovascular diseases, cardiac insufficiency, and
infections and/or inflammations of the lungs and respiratory tract.

[0007]On the one hand, the task is solved by providing the diagnostic
marker CT-proADM (C-terminal fragment of proAdrenomedullin, SEQ ID No.
1), or a partial peptide of fragment thereof, on the other hand, by means
of a method for in-vitro diagnosing and/or stratifying the risk of
diseases. In said method, the CT-proADM (SEQ ID No. 1) marker, or a
partial peptide of fragment thereof, or said marker contained in a marker
combination (panel, cluster) is determined in a patient who is to be
examined (below method according to the invention).

[0008]The term "risk stratification" according to the invention consists
of finding diseased patients having the worse prognosis, for the purpose
of a more intense diagnosis and (follow-up) therapy/treatment of a
disease with the objective of bringing about the most favorable course of
the disease.

[0009]Thus, especially advantageously a reliable diagnosis and/or risk
stratification can be made by means of the method according to the
invention. The method according to the invention allows making clinical
decisions that lead to a quicker diagnosis. Such clinical decisions also
comprise further treatment by using drugs for the treatment or the
therapy of diseases.

[0010]Thus, the invention also relates to a method for the risk
stratification of patients, in particular for the stratification of
patients for clinical decisions, preferably in intensive medicine or
emergency medicine, where time is crucial, and for the hospitalization of
patients.

[0011]In a further preferred embodiment of the method according to the
invention the diagnosis and/or risk stratification is made for prognosis,
for differential-diagnostic early diagnosis and detection, for the
assessment of the severity, and for the evaluation of the course of
diseases accompanying the therapy.

[0012]In a further embodiment of the method according to the invention
body fluid or body tissue, preferably blood, alternatively whole blood,
serum or available plasma, is taken from the patient to be examined, and
the diagnosis is made in vitro/ex vivo, i.e. outside the human or animal
body. Due to the determination of the marker CT-proADM (SEQ ID No. 1), or
partial peptides of fragments thereof, and its existing amount in at
least one patient sample, the diagnosis or risk stratification can be
made.

[0013]Within the scope of this invention "diseases" is to be understood as
illnesses of the human and animal, in particular the mammal. The
descriptions of such diseases, especially human diseases, can be found in
the Pschyrembel, De Gruyter, Berlin 2004.

[0014]Especially advantageous, however, cardiovascular diseases, cardiac
insufficiency, infections and/or inflammations of the lungs and
respiratory tract can be diagnosed and/or stratified within the scope of
this invention.

[0015]The term "cardiovascular diseases" according to the invention
comprises all diseases of the heart and the blood circuit, in particular
such indications as high blood pressure, coronary heart diseases,
especially acute coronary syndrome, (acute) myocardial infarct, angina
pectoris:

[0016]The term "acute coronary syndrome" comprises various phases of
coronary heart disease that are immediately life-threatening. In
particular, this concerns emergency medicine, namely an acute myocardial
infarct and/or angina pectoris, as well as sudden cardiac death. In
addition to the acute myocardial infarct, which, according to WHO
criteria (WHO (1979): Nomenclature and criteria for diagnosis of ischemic
heart disease. Report of the Joint International Society and Federation
of Cardiology/World Health Organization task force on standardization of
clinical nomenclature, Circulation 59 (3): 607-609), is defined as an
acute chest pain event lasting longer than 20 minutes, associated with an
elevation of the ST segment and/or an increase in myocardial enzymes, the
term instable angina pectoris (AP) was coined, which can be read under
"acute coronary syndrome" according to the invention (Hamm C W:
Guidelines: Acute Coronary Syndrome (ACS)--Part 1: ACS without a
persisting elevation of the ST segment. Z Kardiol (2004) 93:72-90).

[0018]Within the context of this invention the term "infections of the
lungs and respiratory tract" particularly means such infections that are
caused by bacteria, viruses, fungi or parasites, for example, indications
such as deep respiratory tract infection (LRTI: lower respiratory tract
infections), bronchitis, pneumonia, sarcoidosis, bronchiectasias,
non-cardiac pulmonary edema.

[0020]Within the scope of this invention pneumonia is understood to be an
acute or chronic inflammation of the lung tissue. Said infection is
caused by bacteria, viruses or fungi, in rare cases also toxically by
inhaling poisonous substances, or immunologically. For the clinician
pneumonia constitutes a constellation of various symptoms (fever or
hypothermia, shivering, cough, pleuritic thorax pain, increased sputum
production, increased breathing rate, hypophonesis, bronchial breathing,
high-frequency rhonchi, pleural rub) in combination with at least one
infiltrate visible on the thorax x-ray (Harrison's Internal Medicine,
published by Manfred Dietel, Norbert Suttorp and Martin Zeitz, ABW
Wissenschaftsverlag [scientific publishing house] 2005).

[0021]Within the scope of this invention the term "infectious diseases of
the lungs and respiratory tract" or "inflammatory diseases of the lungs
and respiratory tract" means indications such as interstitial pulmonary
diseases and lung fibroses, chronic obstructive pulmonary diseases
(COPD), particularly COPD infection exacerbations, bronchial asthma, in
particular infection exacerbations with bronchial asthma, bronchial
carcinoma.

[0022]According to the invention, COPD refers to a group of chronic
diseases characterized by cough, increased sputum and dyspnea under
stress. First and foremost, chronic obstructive bronchitis and pulmonary
emphysema must be mentioned. Both clinical pictures are characterized
especially by an obstruction of the expiration. Moreover, the main
symptom of COPD is colloquially referred to as "smoker's cough." The
invention is especially advantageous in the case of acute exacerbations.

[0024]The "CT-proADM" according to the invention may also feature
modifications such as glycolization, lipidization or derivatizations.

[0025]In a further embodiment the "CT-proADM" (SEQ ID No. 1) may also be
determined with additional markers, with "said marker CT-proADM"
contained in a marker combination (panel, cluster), namely preferably
such marker combinations that already point to a disease. However,
preferred are such markers that in turn point to indications/diseases
preferred within the scope of this invention, and that can bring about a
synergetic effect.

[0026]Thus, the invention relates to such an embodiment of the method
according to the invention, with the determination--additionally selected
by means of at least one additional marker from the group of inflammatory
markers, cardiovascular markers, neurohormonal markers, or ischemic
markers--carried out in a patient who is to be examined.

[0027]According to the invention the inflammatory marker can be selected
from at least one marker from the group of C-reactive protein (CRP),
cytokines, such as for example TNF-alpha, interleukins, such as for
example IL-6, Procalcitonin (1-116, 3-116) and adhesion molecules, such
as VCAM or ICAM, and the cardiovascular marker from of at least one
marker from the group of creatine kinase, myeloperoxidase, copeptin,
myoglobin, natriuretic protein, particularly ANP (or ANF), proANP,
NT-proANP, BNP, proBNP, NT-proBNP, or in each case a partial sequence
thereof, cardiac troponin, CRP. Furthermore, this also includes
(pro)hormones regulating circulation, particularly such as
pro-gastrin-releasing peptide (proGRP), pro-endothelin (proEnd),
pro-leptin, pro-neuropeptide-Y, pro-somatostatin, pro-neuropeptide-YY,
pro-opiomelanocortin, copeptin, or in each case a partial sequence
thereof.

[0028]The ischemic marker can be selected from at least one marker from
the group of troponin I and T, CK-MB. In addition, the neurohormonal
marker can be at least a natriuretic protein, particularly ANP (or ANF),
proANP, NT-proANP, BNP, proBNP, NT-proBNP, or in each case a partial
sequence thereof. Particularly preferred are marker combinations of
CT-proADM with a prohormone, particularly proBNP, NT-proBNP.

[0029]In an additional embodiment of the invention the method according to
the invention can be carried out using parallel or simultaneous
determinations of the markers (e.g. multititer plates with 96 and more
cavities), with the determinations being conducted by means of at least
one patient sample.

[0030]The method according to the invention and its determinations can
also be carried out by means of an automatic analysis device,
particularly a cryptor (http://www.kryptor.net).

[0031]In a further embodiment the method according to the invention and
its determinations can be carried out by means of a rapid test (e.g.
lateral flow test), be it through individual or multi-parameter
determination.

[0032]The invention further relates to the use of CT-proADM (SEQ ID No.
1), or partial peptides or fragments thereof, for the in-vitro diagnosis
and/or risk stratification of diseases, particularly cardiovascular
diseases, cardiac insufficiency, infections and/or inflammations of the
lungs and respiratory tract.

[0033]In a further embodiment the invention relates to the use CT-proADM
(SEQ ID No. 1), or partial peptides or fragments thereof, in cardiac
diagnostics.

[0034]The invention further relates to the use of CT-proADM (SEQ ID No.
1), or partial peptides or fragments thereof, or contained in a marker
combination (panel, cluster) for the in-vitro diagnosis and/or risk
stratification of diseases, particularly cardiovascular diseases, cardiac
insufficiency, infections and/or inflammations of the lungs and
respiratory tract, as well as in particular in consideration of the
above-referenced embodiments. The marker combination can possibly contain
an additional suitable marker.

[0035]A further task is the provision of an appropriate diagnostic device,
or the use of such a device, to carry out the method according to the
invention.

[0036]Within the scope of this invention such a diagnostic device is
understood to be in particular an array or assay (e.g. Immunoassay,
ELISA, etc.), in the broadest sense a device to carry out the method
according to the invention.

[0037]The invention further relates to a kit, or the use of such a kit,
for diagnosing and/or stratifying the risk of diseases in-vitro,
particularly cardiovascular diseases, cardiac insufficiency, infections
and/or inflammations of the lungs and respiratory tract. In said method,
the CT-proADM (SEQ ID No. 1) marker, or a partial peptide of fragment
thereof, or said marker contained in a marker combination (panel,
cluster) is determined in a patient who is to be examined, in particular
in consideration of the above-referenced embodiments. Such detection
reagents include, for example, antibodies, etc.

[0038]Thus, the invention further relates to antibodies, particularly
monoclonal antibodies for the detection of CT-proADM, which bonds
CT-proADM individually, preferably at the bonding sites 1-15 or 19-33 of
SEQ ID. No. 1, in each case independent of one another, or bonds said
CT-proADM at both bonding sites.

[0039]The purpose of the following examples and figures is to explain the
invention in greater detail, without however limiting the invention to
said examples and figures.

EXAMPLES

Immunoassay

Peptide Syntheses

[0040]Derived from the known amino acid sequence of preproADM two areas
were selected (position 153-167, 171-185). The areas--each supplemented
by an N-terminal cystein rest--were chemically synthesized, purified,
inspected for quality by means of mass spectrometry and reversed phase
HPLC, and lyophilized in aliquots based on standard methods as soluble
peptides (JPT Company, Berlin, Germany). The amino acid sequences of the
peptides are called:

[0041]Furthermore, a peptide was synthesized that covers the area position
153-185 of preproADM (PSL33 SLPEAGPGRTLVSSKPQAHGAPAPPSGSAPHFL).

Conjugation and Immunization

[0042]By means of MBS (m-maleimidobenzoyl-N-hydroxysuccinimide ester) the
peptides PSK16 and PHL16 were conjugated to the carrier protein KLH
(keyhole limpet hemocyanine) (see working instructions "NHS
esters-maleimide cross-linkers" PIERCE Company, Rockford, Ill., USA).
Using these conjugates sheep were immunized based on the following
procedure: Each sheep initially received 100 μg of conjugate (weight
measurement relative to the peptide portion of the conjugate) and
subsequently 50 μg of conjugate every 4 weeks (weight measurement
relative to the peptide portion of the conjugate). Starting from the
fourth month after the beginning of the immunization 700 ml of blood was
taken from each sheep every 4 weeks and antiserum was obtained through
centrifugation. Conjugations, immunizations and extractions of antiserum
were carried out by the MicroPharm Company, Carmarthenshire, UK.

Purification of Antibodies

[0043]In a one-step process the peptide-specific antibodies were prepared
from the antiserums that had been extracted starting from the fourth
months after the immunization.

[0044]For this purpose, the peptides PSK16 and PHL16 were first linked to
SulfoLink gel (see working instructions "SulfoLink Kit" PIERCE Company,
Rockford, Ill., USA). In the process, 5 mg of peptide for every 5 ml of
gel was offered for linking.

[0045]The affinity purification of the peptide-specific antibodies from
sheep antiserums against the peptides was carried out as follows:

[0046]At first, the peptide columns were alternately washed three times
with 10 ml of elution buffer (50 mM citric acid, pH 2.2) and a binding
buffer (100 mM sodium phosphate, 0.1% Tween, pH 6.8). 100 ml of the
antiserums were filtered over 0.2 μm and treated with the existing
column material. For this purpose, the gel was quantitatively flushed
from the column with 10 ml binding buffer. Incubation took place over
night at room temperature through rotating. The deposits were
quantitatively transferred to empty columns (NAP 25, Pharmacia, emptied).
The cycles were discarded. Subsequently, washing took place with 250 ml
of binding buffer to remove the protein (protein content of the wash
eluate < 0.02 A280 nm). Elution buffer was placed on the washed
columns, and fractions at 1 ml each were collected. The protein content
of each fraction was determined by means of the BCA method (see working
instructions PIERCE Company, Rockford, Ill., USA). Fractions with protein
concentrations > 0.8 mg/ml were pooled. After determining the protein
of the pools by means of the BCA method, yields of 34 mg for the
anti-PSK16 antibody and 48 mg for the anti-PHL16 antibody were obtained.

[0048]The antibody was further treated for marking with chemo-luminescence
as follows: 67 μl of the antibody solution was treated with 10 μl
of MA 70 acridinium NHS ester (1 mg/ml, Company HOECHST Behring) and
incubated for 15 minutes at room temperature. 423 μl of 1 M glycine
were then added and incubated for an additional 10 minutes. The marking
deposit was then buffer exchanged via a NAP-5 gel filtration column
(Pharmacia) in 1 ml of eluent A (50 mM potassium phosphate, 100 mM sodium
chloride, ph 7.4) based on the working instructions and, in doing so,
freed from low-molecular components. To separate the final rests of
labels not linked to antibodies a gel filtration HPLC was carried out
(column: Waters Protein Pak SW300). The assay was applied and
chromatographed with a flow rate of 1 ml/min with eluent A. With a flow
rate photometer the wave lengths 280 nm and 368 nm were measured. The
absorption ratio of 368 nm/280 nm as a measure for the marking degree of
the antibody amounted to 0.10+/-0.01 at peak. The monomer fractions
containing antibodies (retention time 8-10 min) were gathered and
collected in 3 ml 100 Mm sodium phosphate, 150 mM sodium chloride, 5%
Bovine Serum Albumin, 0.1% sodium acid, pH 7.4

Coupling

[0049]Small irradiated 5 ml polystyrene tubes (Company Greiner) were
coated with purified anti-PHL16 antibodies as follows: The antibody was
diluted in 50 ml of Tris, 100 ml of sodium chloride, pH 7.8, to a
concentration of 6.6 μg/ml. 300 μl of this solution was pipetted
into each small tube. The small tubes were incubated for 20 hours at
22° C. The solution was extracted by suction. Each small tube was
then filled with 4.2 ml of 10 mM sodium phosphate, 2% Karion FP, 0.3%
Bovine Serum Albumin, pH 6.5. After 20 hours the solution was extracted
by suction. Finally, the small tubes were dried in a vacuum dryer.

Implementation and Analysis of the Immunoassay

[0050]Peptide PSL33, which was serially diluted into normal horse serum
(Company SIGMA), served as standard material. Concentrations according to
the initial peptide weight were assigned to the standards manufactured in
this way. The sandwich immunoassay was prepared as follows: 50 μl
standards or assays as well as 200 μl assay buffer (100 mM sodium
phosphate, 150 mM sodium chloride, 5% Bovine Serum Albumin, 0.1%
non-specific ovine IgG, 0.1% sodium acid, ph 7.4) containing 1 million
RLU (relative light units) of the MA70-marked antibody were pipetted into
the small test tubes--each coated with antibodies. Said tubes were
incubated for 2 hours at 22° C. by shaking. Each small tube was
then washed 4 times with 1 ml wash solution (0.1% Tween 20), dripped off,
and the chemo-luminescence attached to the small tubes was measured in a
luminometer (Company BERTHOLD, LB952T; base reagents BRAHMS AG). By using
the software MultiCalc (Spline Fit) the CT-proADM concentrations of the
assays were read at the standard curve.

[0051]Analyt, which can be measured with the described assay, is referred
to as C-terminal proAdrenomedullin (CT-proADM).

Clinical Value

Normal Range

[0052]CT-proADM concentrations were determined in assays of healthy
controls (n=200). The median was at 77.6 pmol/L, the smallest measured
value at 46.6, the largest at 136.2 pmol/L, the 95% percentiles at 58.6
or 113.8 pmol/L, respectively.

Cardiac Insufficiency/Severity

[0053]CT-proADM concentrations were measured in patients with chronic or
acute decompensated cardiac insufficiency. CT-pro ADM concentrations were
associated with the severity of cardiac insufficiency: the average values
of the CT-pro ADM concentrations for the four NYHA severity categories
I-IV were: 85, 107, 140.4 or 242.7 pmol/L (see FIG. 2).

Chronic Cardiac Insufficiency/Diagnosis

[0054]CT-pro ADM values of a collective of 316 patients suffering from
chronic cardiac insufficiency as well as 200 healthy controls were
determined. The receiver-operator-characteristics analysis showed an AUC
of 0.79. At a cut-off value of 122 pmol/L a sensitivity of 39.7% with a
specificity of 98% resulted. At a cut-off value of 113 pmol/L a
sensitivity of 46.3% with a specificity of 95% resulted.

Chronic Cardiac Insufficiency/Prognosis

[0055]CT-pro ADM values of a collective of 316 patients suffering from
chronic cardiac insufficiency were determined. The patients were
monitored over an average time period of 360 days. 42 patients died
during this time period; 274 survived. The best cut-off-value (defined as
the largest product of sensitivity and specificity) to predict mortality
was determined by means of the receiver-operator-characteristics
analysis: 119.7 pmol/L. At this cut-off-value the sensitivity of the
prognosis was 73.2%, the specificity was 62.2%. The likelihood ratio of
dying at a cut-off-value of 119.7 pg/ml was 1.9.

[0056]CT-pro ADM values of a collective of 125 patients suffering from
acute dyspnea were determined. 69 of the 125 patients had cardiac
insufficiency. The receiver-operator-characteristics analysis for the
differential diagnosis of cardiac insufficiency showed an AUC of 0.75. At
a cut-off value of 410 pmol/L a sensitivity of 12.4% with a specificity
of 98% resulted. At a cut-off value of 315 pmol/L a sensitivity of 18.3%
with a specificity of 95% resulted.

Acute Cardiac Insufficiency/Prognosis

[0057]CT-pro ADM values of a collective of 69 patients suffering from
acute decompensated cardiac insufficiency were determined. The patients
were monitored over a time period of 360 days. 21 patients died during
this time period; 48 survived. The best cut-off-value (defined as the
largest product of sensitivity and specificity) to predict mortality was
determined by means of the receiver-operator-characteristics analysis:
192 pmol/L. At this cut-off-value the sensitivity of the prognosis was
66.6%, the specificity was 75%. The likelihood ratio of mortality at a
cut-off-value of 192 pmol/L was 2.5.

TABLE-US-00003
<192 pmol/L >192 pmol/L
Survivors 36 12
Dead 7 14

Myocardial Infarction/Prognosis

[0058]Samples were taken from 287 patients suffering from an acute heart
attack three days after the heart attack had occurred, and the CT-proADM
was measured. The patients were monitored over a time period of 360 days.
During this time period 220 patients experienced no adverse event, 67
died or were rehospitalized due to cardiac insufficiency. The best
cut-off-value (defined as the largest product of sensitivity and
specificity) to predict mortality or rehospitalization due to cardiac
insufficiency was determined by means of the
receiver-operator-characteristics analysis: 161.9 pmol/L. At this
cut-off-value the sensitivity of the prognosis was 67.2%, the specificity
was 79.1%. The likelihood ratio of an adverse event at a cut-off-value of
161.9 pmol/L was 3.2.

[0059]Samples were taken from 142 patients with community-acquired
pneumonia when they were admitted to the hospital, and the CT-proADM was
measured. The patients were monitored over a time period of 70 days, 10
patients died during this time period. CT-proADM concentrations rose with
the PSI (Pneumonia Severity Index), a score for the severity of the
disease (FIG. 3), and were elevated with an average of 135 pmol/L
compared to healthy controls (77 pmol/L). For the prognosis of mortality
the receiver-operator-characteristics analysis yielded an AUC of 0.89.
The best cut-off-value (defined as the largest product of sensitivity and
specificity) to predict mortality was determined by means of the
receiver-operator-characteristics analysis: 194.5 pmol/L. At this
cut-off-value the sensitivity of the prognosis was 100%, the specificity
was 81.2%. The likelihood ratio of mortality at a cut-off-value of 194.5
pmol/L was 5.5.

[0060]CT-proADM of 53 patients suffering from chronic obstructive
pulmonary disease and simultaneous infection of the lower respiratory
tract was measured. With an average of 106 pmol/L the CT-proADM
concentrations in these patients were elevated compared to healthy
controls (77 pmol/L), but lower than those of patients suffering from
pneumonia (see above 135 pmol/L).